7 Pathology of the Cutaneous Vasculitides: A Comprehensive Review Adrienne C. Jordan, Stephen E. Mercer, and Robert G. Phelps The Mount Sinai Medical Center, New York, NY United States of America 1. Introduction Vasculitis has historically been poorly defined and the histological and clinical manifestations are protean, further complicating the diagnostic process. The definitive diagnosis is made by evidence of histologic effacement of a vessel with associated transumural inflammatory infiltrate of that vessel. Vasculitis can be a primary process or secondary to disseminated intravascular coagulation, ulceration, arthropod assault, and/or suppurative infiltrates (for example pyoderma gangrenosum). Vasculitis must further be distinguished from vasculopathies, particularly livedoid vasculopathy and connective tissue diseases (namely scleroderma and systemic lupus erythematosus) in which the primary process is vascular fibrin thrombi of the upper dermal vessels. A necrotizing vasculitis resulting secondary to the thrombotic process can occur, blurring the lines between true vasculitis and vasculopathy. Very few vasculitic processes have pathognomonic histological findings. Often times the dermatopathologist and clinician must work in concert and combine clinical, histological, and laboratory data to determine what the primary process is. As previously stated, histological evidence of inflammatory infiltrate within the vessel wall must be seen in order to diagnose vasculitis. Associated findings include fibrinoid necrosis, endothelial swelling, and endothelial cell apoptosis (Carlson, et al., 2005). Other secondary changes including extravasation of red blood cells, necrosis, ulceration, and neovascularization suggest that there has been vascular damage (Carlson et al., 2005). Associated changes can also be seen in the sweat glands and include basal cell degeneration, necrosis, and basal cell hyperplasia (Akosa & Lampert, 1991). Changes in the adjacent tissue can aid the dermatopathologist in determining what the underlying etiology causing the vasculitis could be. Extravascular granulomas characterized by degenerating collagen bundles surrounded by eosinophils and flame figures (“red” granulomas) are seen in Churg Strauss Syndrome while extravascular granulomas characterized by degenerating collagen bundles surrounded by basophilic debris (“blue” granulomas) are seen in Wegener’s granulomatosis and rheumatoid vasculitis (Carlson, 2010). Dermal lamellar fibrosis can be seen in erythema elevatum diutinum and granulomas faciale (Carlson et al., 2005). Direct immunofluorescence adds another important diagnostic piece of information. Absence of immune complex deposition (pauci-immune vasculitis) is seen in Wegener’s granulomatosis, microscopic polyangiitis, and Churg Strauss syndrome (Carlson, 2010). www.intechopen.com 116 Advances in the Etiology, Pathogenesis and Pathology of Vasculitis Peri-vascular deposition of IgG, IgM, and/or C3 is seen in cutaneous leukocytoclastic angiitis, urticarial vasculitis, and connective tissue disease vasculitis (Carlson et al., 2005). Vascular deposits of IgA are found in Henoch Schonlein purpura while deposition of IgM is seen in cryoglobulinemic vasculitis (Carlson, 2010). Basement membrane zone deposition of immunoglobulins can be seen in urticarial vasculitis and connective tissue disease vasculitis (Carlson et al., 2005). The most common classification system of vasculitides is based on the size of the affected vessel. While biopsy is required for definitive diagnosis, the size of the affected vessel correlates with the cutaneous lesions seen. Large vessel involvement manifests as limb claudication, absent pulses, aortic dilation, bruits, and/or asymmetric blood pressure (Chen & Carlson, 2008). Giant cell (temporal) arteritis and Takayasu’s arteritis are examples of this (Carlson, 2010). Vasculitis involving medium sized (muscular) vessels manifest as subcutaneous nodules, deep ulcers, livedo reticularis, palmar or digital scars, digital gangrene, mononeuritis, erythematous nodules, and aneurysms (Chen & Carlson, 2008). Examples of this include polyarteritis nodosa, Kawasaki disease, and nodular vasculitis (Carlson, 2010). Small vessel vasculitis can be further subdivided into two categories: immune complex mediated vasculitis arising in small post-capillary venules or non-immune complex mediated vasculitis arising in small muscular arteries and arterioles. Small vessel vasculitis appears as purpura, erythema, urticaria, vesiculobullous lesions, superficial ulcers, and splinter hemorrhages (Chen & Carlson, 2008). Examples of this include cutaneous leukocytoclastic vasculitis, Henoch Schonlein purpura, urticarial vasculitis, Churg Strauss vasculitis, Wegener’s granulomatosis, and microscopic polyangiitis (Carlson, 2010). Biopsy location, depth, and timing must be taken into consideration by the clinician to increase the diagnostic yield. Since small vessels reside in the upper dermis while medium sized, muscular vessels are found in the deep dermis and subcutis, a punch or excisional biopsy is required to ensure adequate sampling of all vessel sizes (Carlson et al., 2005). Biopsies performed within 48 hours after the onset of lesions can show a neutrophilic, eosinophilic, or lymphocytic infiltration, depending on the underlying process (Chen & Carlson, 2008). However, after 48 hours, lymphocytes replace the other inflammatory cells, regardless of the underlying etiology and will therefore be non-diagnostic (Chen & Carlson, 2008). Fibrosis, luminal obliteration, and lamination of the vessel wall is seen in healed lesions of vasculitis (Chen et al., 2005). Biopsy from a patient with livedo racemosa must be taken from the center white areas rather then the peripheral red areas since this is where the vascular stenosis can be seen (Carlson, 2010). Biopsy of superficial ulcers should be taken from non-ulcerated skin or from the edge of the ulcer whereas biopsy of deep ulcers should be taken central to the ulcer and include subcutaneous tissue to increase the diagnostic yield of medium sized vessel vasculitis (Chen & Carlson, 2008). 2. Small vessel vasculitis 2.1 Immune complex mediated vasculitis in post capillary venules 2.1.1 Cutaneous leukocytoclastic angiitis Cutaneous leukocytoclastic angiitis (CLA) is also known as cutaneous leukocytoclastic vasculitis, hypersensitivity vasculitis/angiitis, allergic vasculitis, and necrotizing vasculitis (Carlson & Chen, 2006). The Chapel Hill Consensus Conference (CHCC) defines CLA as an isolated cutaneous leukocytoclastic vasculitis in the absence of systemic vasculitis (Carlson et al., 2005). Patients are typically middle aged adults with a recent history of exercise in hot www.intechopen.com Pathology of the Cutaneous Vasculitides: A Comprehensive Review 117 weather (Chen & Carlson, 2008). Less than 10% of patients may present with renal or gastrointestinal involvement, however, this systemic vasculitis variant of CLA has yet to be formally recognized (Carlson, 2010). Etiology may be secondary to medications, viral upper respiratory infection, or collagen vascular diseases; however, in the majority of cases no etiology will be identified (Grunwald et al., 1997). The cutaneous manifestations include crops of palpable purpura over the lower extremities associated with pruritus, stinging, tenderness, or burning (Chen & Carlson, 2008). Rarely patients may present with erythema and hemorrhagic bullae on the lower extremities (Carlson, 2010). Areas of ecchymoses and hyperpigmenation are seen as the lesions resolve over a period of 3-4 weeks (Chen & Carlson, 2008). The general pathologic features of CLA on a skin biopsy include fibrin deposits, neutrophilic perivascular infiltration of small vessels, and nuclear debris (leukocytoclasia) (Carlson & Chen, 2006) (see Figures 1 and 2). Hemophagocytosis can also be seen (Draper & Morgan, 2007). The pathologic features of CLA change with temporal evolution. Early lesions are characterized by a neutrophil dominant vasculitis in the upper to mid dermis which then progresses to a mononuclear predominant vasculitis within 120 hours after the onset of the lesions (Zax et al., 1990) (see Figure 3). Epidermal involvement including vesicle formation and ulceration can also be identified (Grunwald et al., 1997). The healing lesions show regenerative endothelial cells, fibrin deposits within vessel walls, and a mild monocytic perivascular infiltrate (Grunwald et al., 1997) (see Figure 4). The other classic features of CLA including extravasation of erythrocytes, fibrinoid necrosis, and epidermal necrosis fade as the lesions age (Zax et al., 1990). Rarely a necrotizing venulitis can be seen extending through the mid and deep dermis (Carlson, 2010). Fig. 1. Cutaneous Leukocytoclastic Angiitis. Small vessel vasculitides demonstrate many common features including fibrinoid necrosis, marked inflammation, leukocytoclasia and red cell extravasation (H&E, 40x). www.intechopen.com 118 Advances in the Etiology, Pathogenesis and Pathology of Vasculitis Fig. 2. Cutaneous Leukocytoclastic Angiitis. Neutrophilic perivascular infiltration of small vessels with accompanying leukocytoclasia consisting of karryorhectic nuclear debris (H&E, 400x). Fig. 3. Cutaneous Leukocytoclastic Angiitis. Fibrinoid necrosis of the vessel walls is characteristic (H&E, 400x). www.intechopen.com Pathology of the Cutaneous Vasculitides: A Comprehensive Review 119 Fig. 4. Cutaneous Leukocytoclastic Angiitis. Intravascular fibrin thrombi are common and may be